Lowering the Risk of Operative Complications Using Atorvastatin Loading Dose (LOAD)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Hospital do Coracao
Sponsor:
Information provided by (Responsible Party):
Instituto de Ensino e Pesquisa, Hospital do Coracao
ClinicalTrials.gov Identifier:
NCT01543555
First received: February 27, 2012
Last updated: August 22, 2014
Last verified: August 2014
  Purpose

Patients undergoing some kinds of surgeries are at increased risk of developing a myocardial infarction and other serious cardiovascular complications during and after the procedure. Atorvastatin, a drug used to lower cholesterol levels, might reduce this risk. The objective of this study is to evaluate if starting atorvastatin as close as possible to surgery, but not longer than 18 hours ahead, and taking this drug for at least 7 days thereafter can reduce the risk of a composite end point of myocardial infarction, atrial fibrillation, stroke or death in the postoperative period.


Condition Intervention Phase
Myocardial Infarction
Peripheral Vascular Disease
Aortic Aneurism
Drug: Atorvastatin
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Multicenter Randomized Controlled Trial of Loading Dose Statins for the Prevention of Cardiovascular Complications in High-Risk Non-Cardiac Surgery

Resource links provided by NLM:


Further study details as provided by Hospital do Coracao:

Primary Outcome Measures:
  • Major Adverse Cardiovascular Events (MACE) [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    Proportion of patients with non-lethal myocardial infarction, atrial fibrilation, stroke or death during hospital stay up to 30 days.


Secondary Outcome Measures:
  • Cardiovascular mortality [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    Mortality attributed to progression of cardiovascular diseases or sudden death in an otherwise healthy subject

  • Stroke [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    New neurologic symptom with compatible lesion on brain imaging and confirmation by a neurologist of the diagnosis of stroke

  • Liver enzymes [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    Elevation of AST and ALT after randomization

  • CPK [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    Elevation of CPK after randomization, as a substitute for rhabdomyolysis

  • Myalgia [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    Myalgia as a substitute for rhabdomyolysis

  • Myocardial infarction [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    Rate of myocardial infarction as defined by any 2 of: typical chest pain OR typical ECG changes (ST-segment depression, ST-segment elevation, new Q waves, transitory T wave inversion) OR new rise in troponin levels (CK-MB levels if unavailable) OR new wall motion abnormality on echocardiogram. Pathological confirmation of myocardial necrosis on necropsy will also be accepted

  • VTE - Venous Thromboembolism [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    Any deep vein thrombosis or pulmonary embolism confirmed by adequate images on ultrasound, computed tomography or angiography

  • Major bleeding [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    Any non-traumatic retro peritoneal, intraocular, intramedullary or intracranial bleeding in the first 48 hours after surgery or any need for re-operation for hemosthasis.

  • Troponin levels [ Time Frame: 72hs ] [ Designated as safety issue: No ]
    Absolute values of troponin (I, T, hsI, hsT depending on the assay available in each center) once a day in the first 3 days after surgery. Surrogate for myocardial lesion.

  • Clinically relevant atrial fibrillation [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    A newly diagnosed atrial fibrillation that results in angina, heart failure, hypotension, or that requires treatment with an anti-arrhythmic drug or electric cardioversion


Estimated Enrollment: 2500
Study Start Date: November 2012
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: November 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Atorvastatin active
Loading dose atorvastatin (80mg) given to the patient as close as possible to the procedure, but not longer than 18 hours before. A second dose (40mg) of atorvastatin at least 12 hours after the loading dose. Daily doses of atorvastatin (40mg) initiated in the next day after the second dose, and maintained for the following seven days.
Drug: Atorvastatin
80mg atorvastatin before surgery, than 40mg atorvastatin 12hs after the loading dose, than 40mg atorvastatin every night for 7 days
Other Names:
  • Liptor (R)
  • Kolevas (R)
Placebo Comparator: Placebo
Loading dose of matching placebo given to the patient as close as possible to the procedure, but not longer than 18 hours before. A second dose of matching placebo at least 12 hours after the loading dose. Daily doses of matching placebo initiated in the next day after the second dose, and maintained for the following seven days.
Drug: Placebo
80mg placebo capsule before surgery, 40mg placebo capsule 12hs after the loading dose, 40mg placebo capsule every night for 7 days
Other Name: Standard care

Detailed Description:

Cardiovascular complications, such as myocardial infarction (MI) and stroke are common in non-cardiac surgery, with mean incidences of 7% for high-risk patients. Despite a significant reduction of 30% in the rates of MI, beta-blockers have been associated with a prohibitive 117% increase in the risk of stroke in this situation. Since the evidence supporting the use of aspirin, calcium-channel blockers and clonidine is also weak, it is still unclear whether pharmacologic interventions are effective in this population.

Data from observational studies have shown that chronic users of statins have a 20%-30% lower incidence of periprocedural MI and 3 prospective randomized controlled trials (RCTs) have shown a 48% risk reduction for the initiation of statins 30 days before surgery. However, this intervention demands a 1-month delay in the procedure, which makes it unfeasible in many situations, such as emergency.

Experimental data show that statins have acute anti-inflammatory properties, which promote the stabilization of atherosclerotic lesions and, therefore, might reduce the risk of MI even after shorter use. A single loading dose of statins as early as 12hs before the procedure has been associated with a 44% reduction in the rate of MI in patients undergoing elective percutaneous coronary intervention (PCI), making it a promising intervention for patients undergoing non-cardiac surgery. This study was designed to test the effectiveness of atorvastatin started before a non-cardiac surgery on the reduction of perioperative cardiovascular events.

  Eligibility

Ages Eligible for Study:   40 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients older than 40 years-old undergoing non-cardiac surgery with an expected hospital stay of at least 24hs and that fulfills any one of the following criteria:

A) Established vascular disease:

i) Major vascular surgery ii) All types of surgery in patients with overt atherosclerosis (any significant or symptomatic coronary, cerebral or peripheral artery disease)

B) Without established vascular disease:

At least 3 risk factors for cardiovascular complications:

  1. Major surgery;
  2. Emergency surgery;
  3. Previous history of heart failure;
  4. diabetes;
  5. Arterial hypertension;
  6. Smoking habit along the last two years;
  7. chronic kidney disease (creatinine greater than 2mg/dl);
  8. Patients older than 70 years.

Exclusion Criteria:

  • Previous intolerance to statins
  • Current rhabdomyolysis
  • Current use of statins
  • Severe Liver Failure (CHILD-PUGH SCORE C)
  • Breast-feeding or pregnancy
  • Low-risk surgeries
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01543555

Contacts
Contact: Otávio DG Berwanger, MD, PhD +55 11 30536611 ext 8201 oberwanger@hcor.com.br
Contact: Dimas T Ikeoka, MD, PhD +55 11 30536611 ext 8239 dikeoka@hcor.com.br

Locations
Brazil
Hospital do Coração Recruiting
São Paulo, SP, Brazil, 04005-000
Contact: Otavio Berwanger, MD, PhD    3053-6611 ext 8237    oberwanger@hcor.com.br   
Contact: Dimas T Ikeoka, MD, PhD    3053-6611 ext 8239    estudo.load@gmail.com   
Principal Investigator: Otávio Berwanger, MD, PhD         
Sponsors and Collaborators
Hospital do Coracao
Investigators
Study Director: Otávio Berwanger, MD, PhD Hospital do Coração
Principal Investigator: Diogo DG Bugano, MD Hospital do Coração
Study Chair: Rafael M Soares, MSc Hospital do Coração
Study Director: Renato D Lopes, MD Phd Brazilian Clinical Research Institute
Principal Investigator: Sabrina B Pereira, MD, MSc Hospital do Coração, SP
Principal Investigator: Dimas T Ikeoka, MD, Post-Doc Hospital do Coração, SP
  More Information

Publications:
Patti G, Cannon CP, Murphy SA, Mega S, Pasceri V, Briguori C, Colombo A, Yun KH, Jeong MH, Kim JS, Choi D, Bozbas H, Kinoshita M, Fukuda K, Jia XW, Hara H,Cay S, Di Sciascio G. Clinical benefit of statin pretreatment in patients undergoing percutaneous coronary intervention: a collaborative patient-level meta-analysis of 13 randomized studies. Circulation. 2011 Apr 19;123(15):1622-32. Epub 2011 Apr 4. PubMed PMID: 21464051.

Responsible Party: Instituto de Ensino e Pesquisa, Research Institute HCor, Hospital do Coracao
ClinicalTrials.gov Identifier: NCT01543555     History of Changes
Other Study ID Numbers: 02/15/2012
Study First Received: February 27, 2012
Last Updated: August 22, 2014
Health Authority: Brazil: Ethics Committee

Keywords provided by Hospital do Coracao:
myocardial infarction
statin
perioperative care
peripheral vascular diseases
anesthesiology

Additional relevant MeSH terms:
Infarction
Myocardial Infarction
Vascular Diseases
Aortic Aneurysm
Peripheral Vascular Diseases
Peripheral Arterial Disease
Ischemia
Pathologic Processes
Necrosis
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Aneurysm
Aortic Diseases
Atherosclerosis
Arteriosclerosis
Arterial Occlusive Diseases
Atorvastatin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Lipid Regulating Agents
Therapeutic Uses
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 30, 2014